Mouthwash solution

ABSTRACT

PCT No. PCT/FI87/00092 Sec. 371 Date Mar. 2, 1988 Sec. 102(e) Date Mar. 2, 1988 PCT Filed Jul. 7, 1987 PCT Pub. No. WO88/00044 PCT Pub. Date Jan. 14, 1988.A mouthwash solution to prevent enrichment, in the oral cavity on mucous membranes and dental surfaces, of metals, particularly heavy metals. The mouthwash solution contains water-soluble alkali metal or alkali earth metal salt or salts, particularly the Na, K, Mg or Ca salt, or their complex salt of an amino(carboxylic) acid forming with heavy metal ions stable, water-soluble complex compounds in oral cavity conditions.

BACKGROUND OF THE INVENTION

The present invention concerns a mouthwash solution intended to preventenrichment of heavy metals in the oral cavity on mucous membranes anddental surfaces.

In corrective dental care metallic materials are used in rather greatprofusion, such as tooth fillings and crown materials; the number ofdifferent materials is estimated to be more than one hundred. Usuallythese materials are composed of four or five different metals andcompounds thereof.

For metallic filling material is used amalgam filling, which istypically prepared of mercury (contribution about 45-55%) and of apremix, which typically has had the composition: Ag 67-70%, Sn 25-29%,Cu 0-5%, Zn 0-2%. In modern amalgam fillings, however, copper tends,owing to price considerations, to replace silver, its quantity risingeven up to 30%.

Actual prostheses, i.e., crowns, are made outside the oral cavity bycasting a metal duplicate corresponding in its structure to theextracted tooth, or a metal blank which is overlaid with ceramic enamelto simulate the structure of the tooth. High-gold materials havetraditionally been the best material to serve this purpose. In order toreplace gold and to optimize the properties of the alloy (mechanicalcharacteristics, castability, corrosion resistance, metal/ceramic bond,thermal expansion) other metals, also less noble ones, have to be added(Pt, Pd, Ag, Cu, Fe, Sn, Zn, In, Ga, etc.). The composition of thematerials which are used and the contribution of base metals varyconsiderably both from manufacturer to maunfacturer and in accordancewith the requirements imposed on the prosthesis.

The problem in dental care of the kind just described have been allergicreactions of patients, especially in risk groups like asthmatics, who onthe whole are disposed to allergic reactions. The cause responsible forthese reactions is the dissolving of heavy metals in the mouth fromdental care materials. These heavy metal effusions tend to becomeenriched and to accumulate in the oral cavity on dental surfaces,darkening them, and particularly on mucuous membranes.

We have found that those patients in whom allergic symptoms have beenobserved have in their saliva and in their oral cavity metal residues inquantities which should be reduced. In our studies we have establishedthe cause of certain diseases of the oral mucous membranes to beallergic irritation from metals. It is also likely that contact allergyin the oral cavity may acerbate the cell picture of incipient cancer ofthe mouth.

We have observed in our studies that all metals here in question causeallergies of the oral cavity. One patient may moreover simultaneouslyhave allergies from several metals.

Nobler metals and noble metal-based homogeneous metal alloys are not inthemselves likely to react with saliva, which a weak electrolyte and oneof which the acidity is close to neutral.

The situation is substantially changed, in principle, when there areconcomitantly several metallic materials in the mouth which differ as totheir electrochemical nature.

The difference between metals in electrochemical respect is commonlydescribed with the aid of the so-called electrochemical potentialseries, which gives a simple picture of the differential potentialsacting between different metals. Thus, for instance, when gold andcopper are in mutual contact said differential potential tends todissolve copper, which in itself would be comparatively stable in thecircumstances.

The amount in which heavy metals are dissolved in saliva is dependent ona number of factors, e.g. on how direct is the contact between themetals, and on the homogenity of the alloy. Even from an alloy rich innoble metals there may be even rapid dissolving in saliva of componentswhich are only little less noble. Of course, conditions for dissolutionof heavy metals are particularly favourable in connection with toothfilling, burnishing and bridge and crown grinding and thereafter.

SUMMARY OF THE INVENTION

The object of the present invention is to prophylactically preventallergic reactions started by heavy metals and the darkening of dentalsurfaces, by preventing enrichment and accumulation of heavy metal ionsin the oral cavity.

The mouthwash solution of the invention is, in order to achieve this,characterized in that it contains water-soluble alkali metal or earthalkali metal salt or salts, in particular Na, K, Mg or Ca salt, or theircombination salt or a mixture thereof, of an amino(carboxylic) acid oracids forming with heavy metal ions stable, water-soluble complexcompounds in the conditions prevailing in the oral cavity.

The salt is preferably 2Na-Ca-EDTA, Mg salt of EDTA, Na salt of NTA, orNa salt of EDTA. In other words, the salt is preferably a salt of anamino(carboxylic) acid.

Additionally, the acidity, i.e. the pH of the mouthwash solution, haspreferably been adjusted. More specifically, the solution is adjusted sothat the pH range is within about 5.5-8.5, more preferably between about6.5-7.5. Furthermore, the content of the salt in the mouthwash solutionis preferably about 1-10%, more preferably about 2-5%.

The mouthwash solution of the invention is used by washing the oralcavity frequently enough with a solution containing an appropriatequantity of a substance which binds the heavy metals in stable,water-soluble complex salts, preferably in chelates. With suchtreatment, the heavy metals will be eliminated from the organism afterwashing, together with the washing water, and owing to the shortduration of the treatment the metallic filling and prosthetic materials,or the enamel surfaces of the teeth, suffer no damage. However, a moreintensive treatment may even be recommendable in connection with toothfilling or burnishing and with bridge or crown grinding.

A very great number of compounds efficiently complexing heavy metal ionsare known. A considerable number of these act very selectively, that is,they complex only metal ions of a certain kind and within certain pHranges and under certain reaction conditions, while other complexformers produce salts of which the stability depends with differentmetals selectively, though strongly, on the acidity of the solution.

It is important from the viewpoint of the present invention that whenselecting a suitable complex former for use in a mouthwash solution, itis checked that it does complex specifically in oral pH conditions thoseheavy metals which are desired. Tables exist which serve this purpose.The complex salt should moreover be water-soluble under the conditionsin this case.

In most instances, however, as was observed before and as noted above,many metals cause allergies and one patient may be simultaneouslyallergic to several metals. Usually there is also no accurateinformation about the heavy metals spectrum in the oral cavity at theparticular time.

Thus, it is advantageous, as taught by the invention, to use complexformers which are active in a broad range. Since chelate (complex)formers with broad action operate as efficient recoverers of heavy metalions in the oral cavity, the invention also affords the advantage thaton the basis of the composition of the wash solution a picture isobtained of the heavy metals spectrum in the oral cavity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Among broad-action, efficient complex formers, the following may beparticularly mentioned: iminodiacetic acid (IDA), nitrilotriacetic acid(NTA), -iminotriacetic acid (ITA), ethylenediamine-N,N'-diacetic acid,ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaaceticacid (DPTA), 2-hydroxyethylethylenediaminetriacetic acid (HEDTA),ethylenediamine (En), N,N'-diethylenediamine, diethylenetriamine (Den),diethylenetetraamine (Trien), β,β',β"-triaminotriethylamine (Tren),propylenediamine. Further agents which are efficient in broad action aresalicylic acid, salicylaldehyde and derivatives, citric acid,acetylacetone, o-aminophenol and condensed phosphates.

Those amino(carboxylic) acids which are important as regards usabilityare suitable for use towards the purpose of the present invention in theform of a solution in which they occur as alkali or alkali earth saltsor complex salts thereof, e.g. 2Na-Ca-EDTA. The acidity of the solutionshould be compatible with oral environment, neutralizing being mostadvantageously effected with NaOH. The solution will contain NA-Ca saltof EDTA when neutralizing the CaH₂ -EDTA solution with NaOH. Asubstantial part is present in the 2Na-Ca-EDTA form. A typical pictureof the properties of amino(carboxylic) acids is given by Table 1. Thetable reveals that the stability of the complex salts of EDTA dependsvery strongly, though non-selectively, on the acidity of the solution.Under typically oral conditions (pH=6.5-7.5), EDTA chelate heavy metalions efficiently. Mercury, the EDTA chelate of which is one of the moststable, is missing in the table.

It is characteristic of EDTA and NTA that when these acids areneutralized e.g. with NaOH there is an exactly determined acidity (pH)of the solution corresponding to any given degree of neutralizing. It istherefore essential to state this, e.g. from the viewpoint ofdetermining the composition of the Na salt.

                                      TABLE 1                                     __________________________________________________________________________    pM values for EDTA                                                            EDTA, 10% excess                                                              Ph Cu.sup.2+                                                                         Ni.sup.2+                                                                        Pb.sup.2+                                                                        Co.sup.2+                                                                         Zn.sup.2+                                                                         Cd.sup.2+                                                                         Fe.sup.2+                                                                        Fe.sup.3+                                                                        Mn.sup.2+                                                                         Ca.sup.2+                                                                         Mg.sup.2+                              __________________________________________________________________________    2  3.9 4.0                                                                              3.8                                                                              2.2 2.2 2.3 2.1                                                                              10.7                                                                             2.0 2.0 2.0                                    3  6.7 6.8                                                                              6.6                                                                              4.5 4.8 3.7 3.7                                                                              13.5                                                                             2.7 2.0 2.0                                    4  8.9 9.0                                                                              8.8                                                                              6.7 6.7 7.0 5.1                                                                              15.7                                                                             4.5 2.3 2.0                                    5  10.8                                                                              10.9                                                                             10.8                                                                             8.6 8.6 9.0 7.1                                                                              17.6                                                                             6.0 3.8 2.4                                    6  12.6                                                                              12.8                                                                             12.6                                                                             10.5                                                                              10.5                                                                              10.7                                                                              8.8                                                                              19.5                                                                             7.3 5.5 3.8                                    7  13.9                                                                              14.1                                                                             13.9                                                                             11.8                                                                              11.8                                                                              12.1                                                                              10.2                                                                             20.8                                                                             9.1 6.3 4.9                                    8  15.0                                                                              15.1                                                                             14.9                                                                             12.8                                                                              12.8                                                                              13.1                                                                              11.3                                                                             21.8                                                                             10.1                                                                              7.3 5.4                                    9  16.0                                                                              16.1                                                                             15.9                                                                             13.8                                                                              13.8                                                                              14.1                                                                              12.4                                                                             22.8                                                                             11.1                                                                              8.3 6.4                                    10 16.8                                                                              17.0                                                                             16.8                                                                             14.6                                                                              14.6                                                                              15.0                                                                              14.2                                                                             23.7                                                                             12.0                                                                              9.2 7.2                                    11 17.2                                                                              17.3                                                                             17.2                                                                             15.0                                                                              15.0                                                                              15.3                                                                              16.4                                                                             25.5                                                                             12.3                                                                              9.5 7.6                                    __________________________________________________________________________

In the following an example is presented in which the above-mentionedcompounds have been active owing to their broad action spectrum althoughthe background information was most incomplete.

EXAMPLES Patient 1

A 63 years old housewife attended for investigations because ofintensive glossalgic pain and smarting of maxillary gums and buccal andlabial mucuosa. There was a slight swelling under her eyes and shecomplained of unpleasant thickness of the face. The breathing wasaccording to her difficulted because of sinusitis like feeling. Thesemajor complaints had lasted for two years, since she had got a ten unitslong metal-ceramic bridge in the maxilla. Her difficulties began in1979, when she got a chromium cobalt denture in lower jaw resulting asbleeding allergic ulcerations. After refusing the denture she got a newone at the university clinic with similar results. A new casting with agold bar was constructed. When this broke during the first month it wasbased by cold curing acrylic with a bleeding allergic ulceration as aresult. Prior to these reactions, only her allergy to nickel was known.

A complete ten units bridge was made by private dentist in the lower jawfrom C-gold casting and this was tolerated well. Immediately after this,another ten units bridge was constructed in upper jaw frommetal-ceramics. Soon after the insertion severe pains and smarting withdescripted symptoms of the head region began. Several root canaltreatments and paradental operations were performed by specialistswithout relief.

When the closer investigation began, her glukose tolerance test andserum B 12 levels showed to be normal. Eosinofile count of the fullblood was 525 (normal variation b 40-440) and differential leukosytecount 0.13 (variation 0.00-0.07). The serum immunoglobules seemed to benormal: S-IGA 1.7 (0.9-4.5), S-IGG 12.0 (8.0-18.0), S-IGM 1.6 (0.6-2.8).

A 5% Ca-Na-2-EDTA in water solution was introduced for differentialdiagnostics. She rinsed her mouth twice daily by 10 ml of solution fortwo minutes. After spitting out she washed her mouth by tap water.Within three days the pain and smarting symptoms disappeared. Withinthree days the pain and smarting symptoms disappeared. After 3 months,August 1986 the blood controls showed normalization of eosinofiles from525 to 194 and the differential count of leucosytes from 0.13 to 0.09according to the eosinofiles. In a second control after three moremethods the eosinofile count of leukosytes had gone down to 0.06 and theblood eosinofiles were still at 194.

Prior to the treatment skin patch tests were performed to revealpossible allergies. There were positive reactions to 5% nickel sulfateby 4+, 1% chromium cloride by 3+, 5% tin chloride by 2+,N-Etyl-P-Toluensulfoamide by 2+ and P-tolydietanolamine by 2+. Becauseof the supposed irritation to tin instead of allergy, the tinconcentration was diluted to 2.5 and 1%, which did not alter the readingof the patch test.

On the absolute request of the patient, the upper bridge was taken offand constructed again of a traditional C-gold alloy. She felt well withthis material. On further request, the composition of the ceramic metalwas analyzed at the Technical University of Helsinki by an EnergyDispersive Roentgen Spectrophotometry with a semiquantitative result ofthe non casted alloy containing 4.8% tin and the casted and oxidatedalloy containing site dependent variations of great amounts of tin. Theceramic was shown to contain 8-10% tin, the richer sites being on thecolored cervical areas, where the mixture of metal oxides was used ascharacterization. In addition, the ceramic contained maximum 1% nickelon some points of the surface. The content of copper was varying between1-3%.

Patient 2

A 24 years old man had been in hospital investigations four years beforebecause of atopic reactions and asthma. He was found to be allergic tohay and pollens. Two years later this man with red hair got recurrentaphthous stomatitis and swelling around his eyes. The lower lip wasswollen and anaesthetic. He was referred to ear and nose clinic where asuspicion diagnosis remained for Melkerson-Rosenthal syndrome orsarcoidosis. During the next two years he had daily a slight rise intemperature, he felt tired and was suffering itching gingival pains andheadache.

In blood tests the leukosyte count was 3.6, of which eosinofiles counted2%. Wholeblood eosinofiles counted 44 (variation 40-440). Patch testsfor allergy were performed from the Swedish dental tray of Kemoteknik byspecialist in dermatology. Positive tests were achieved by 30% propyleneglycol (2+) and tin chloride 5% (2+). The skin reactions wereinterpreted as weak allergic reactions.

When his anamnestic data were reviewed, he told that about five daysafter each visit at his dentist the reactions came. He had receivedseveral silver amalgam fillings or crowns of amalgam.

One lower molar was extracted and a marked amalgam tattoo was seen atplace. In biopsy of the pigment only foreign body reactions were seenwitout allergic findings. Gingival margins in lower jaw were slightlyhyperplastic without gingivitis. In biopsy of this gingiva, noinflammation or foreign body reaction was seen.

A metal antagonist therapy by chelating mouth rinse was performed bytwice a day rinsing. This preparation was calcium saturated Ca-Na-2-EDTAsolution with no activity to calcium ions. After the first week oftreatment the gingival smarting disappeared, the patient had no feverand felt well. Mouthrinsing was performed for two months. No aphthousattacks or other symptoms have appeared. Patient's symptoms areconcluded to be connected to the silver amalgam fillings or otherirritation of metallic nature.

We claim:
 1. In a method for preventing enrichment of metals, in an oralcavity on mucous membranes and dental surfaces, the improvementcomprising the step ofadministering to patients allergic to metalsdissolving from their metallic amalgam with fillings, bridges, crowns,dentures, or other prostheses until the patients' symptoms of allergicreaction to the metal are concluded, a mouthwash solution containing atleast one water-soluble alkali metal or alkali earth salt of anamino(carboxylic) acid selected from the group consisting of salts ofiminodiacetic acid (IDA), nitrilotriacetic acid (NTA) or iminotriaceticacid (ITA), ethylenediamine-N,N'-diacetic acid,ethylenediaminetetraacetic acid (EDTA), diethylene-triaminepentaaceticacid (DPTA), 2-hydroxyethylethylenediamine-triacetic acid (HEDTA),ethylenediamine (EN), N,N'-diethylenediamine, diethylene-triamine (DEN),diethylenetetraamine (TRIEN), beta,beta',beta"-triamino-triethylamine(TREN), propylenediamine, salicylic acid, salicylaldehyde andderivatives thereof, citric acid, acetylacetone, o-aminophenyl, andcondensed phosphates, and mixtures thereof, in an amount effective intwice a day mouthrinse for forming, with heavy metal ions, stable,water-soluble complex compounds under oral cavity conditions.